Dosage regimen, medication dispensing package and uses thereof for the treatment of major depressive disorder

ABSTRACT

This invention provides an oral dosage regimen for the treatment of depression, a pharmaceutically acceptable medication dispensing package containing multiple dosage units of medicaments comprising an oral dosage regimen of D-cycloserine for the treatment of depression, a pharmaceutical composition comprising D-cycloserine formulated for oral administration providing a dosage of 1000 mg/day alone or in combination with antidepressant agents and uses thereof.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a 371 national stage entry of PCT/IL2012/050034filed on Jan. 30, 2012, which claims benefit of U.S. 61/437,700, filedon Jan. 31, 2011, and U.S. 61/494,907, filed on Jun. 9, 2011. Theabove-referenced applications are incorporated by reference in itsentirety.

BACKGROUND OF THE INVENTION

Major depression is a clinical syndrome that includes a persistent sadmood or loss of interest in activities, which persists for at least twoweeks in the absence of treatment. Symptoms of major depression aretypically measured using rating scales such as the Hamilton DepressionRating Scale (HAM-D) or the Beck Depression Inventory (BDI). In additionto including symptoms relevant to depressed mood, the HAM-D alsocontains symptoms sensitive to psychosis, including items for guilt,depersonalization/derealization and paranoia. Major to depression mayalso be associated with symptoms of anxiety, which may be measured withrating scales such as the Hamilton Rating Scale for Anxiety (HAM-A).Depressive disorders are divided in major depression (MDD) and bipolardepression (BPD). Major depression may also occur with and withoutmelancholic features. In addition, depressive symptoms may occur in thecontext of anxiety disorders such as generalized anxiety disorder,dissociative disorders, personality disorders or adjustment disorderswith depressed mood (DSM-IV).

Current treatments for major depression consist primarily of olderantidepressants, such as monoamine oxidase inhibitors (MAOI) andtricyclic antidepressants (TCAs) (e.g. imipramine, amitryptiline,desipramine, clomipramine) that were first developed in the 1960's, andnewer agents such as tetracyclic antidepressants (TeCAs) (e.g.,mianserin, mirtazapine), serotonin (SSRI) and serotonin/norephinephrine(SNRI) reuptake inhibitors (e.g., fluoxetine, fluvoxamine, paroxetine,citalopram, escitalopram, duloxetine, venlafaxine, dapoxetine,indalpine, valzodone). MAOIs and TCAs are considered “broader spectrum”agents than SSRIs/SNARIs that were developed subsequently.

However, current treatment approaches have severe limitations. Only60-65% of patients respond to the initial regimen and among thoseresponding, less than half either reach remission or becomesymptom-free. Individuals not responding to a first course ofantidepressant treatment are often switched to a different drug, withresults that are generally modest and incremental.

Antipsychotics may be divided into typical (e.g. chlorpromazine,haloperidol) vs. atypical (e.g. risperidone, olanzapine, quetiapine,aripiprazole, clozapine) based upon receptor binding, preclinicaleffects and side effect profile. Several antipsychotic agents, includingquetiapine, risperidone, olanzapine and aripiprazole are also indicatedfor treatment of depression in both major depressive and bipolardisorders.

TCAs and SSRIs show approximately equal efficacy in treatment ofnon-melanchoic forms of depression, suggesting overlapping butdifferentiable mechanisms of action. TCAs as a group show limitedantipsychotic activity, alone or in combination with antipsychotics, butmay be effective in treating persistent depressive symptoms instabilized schizophrenia patients. TCAs have been shown to worsenpsychosis in acutely decompensated schizophrenia patients, but to berelatively without effect on psychosis during the chronic phase ofillness. In contrast, SSRIs and TeCAs may improve psychotic symptoms inaddition to treatment of depression in refractory schizophrenia,suggesting a differential mechanism of action and mild antipsychoticpotency.

Treatment-refractory depression refers to a form of depression thatresponds poorly to currently available treatments (e.g.,http://www.nimh.nih.gov/trials/practical/stard/index.shtml June 2011)and which may have different underlying etiopathological mechanismscompared with other forms of depression. Combinations of antidepressantshave not been shown to be superior to monotherapy for refractorydepression and typically increase risk of side effects and are notrecommended.

Risk for suicide is significantly increased in depressive disorders, butmay respond differentially to medication versus depressive symptoms as awhole. When suicide occurs, it is often accompanied by feelings ofworthlessness or inappropriate guilt, as well as recurrent thoughts ofdeath or suicidial ideation and guilt is an accepted proxy for suicide.While the risk of suicide increases in subjects with a depressivedisorder, medications used to date to typically treat depressivedisorders paradoxically increase suicidal tendencies.

Most current theories of depression focus on serotonergic and/ornoradrenergic brain systems. Glutamate is an alternative brainneurotransmitter that has been studied to a limited degree inrelationship to depression or other affective disorders. Glutamate bindsto several receptor types including N-methyl-D-aspartate type glutamatereceptors (NMDAR). NMDAR contain multiple binding sites including anagonist site for glutamate and an allosteric modulatory site (akaglycineB receptor, strychnine-insensitive glycine receptor) sensitive tothe endogenous brain amino acids glycine and D-serine. Agonists at theglycine site increase NMDAR activation in response to glutamate whileantagonists decrease NMDAR activation.

Functional agonists and antagonists at the glycine site can beidentified using well-validated electrophysiological assays such asmodulation of NMDA-receptor mediated responses to NMDA glutamate-siteagonists, or radioreceptor assays, such as modulation of binding to theNMDA PCP-receptor channel binding site. Glycine site agonists andantagonists can also be distinguished based upon both electrophysiologyand receptor binding from compounds such as phencyclidine (PCP) orketamine that bind to the channel site (aka PCP receptor, uncompetitiveantagonist site) of the NMDAR. Effective agonists and antagonists may beidentified, for example, as compounds with <100 nM affinity for theirtarget and >10-fold selectivity vs. other relevant targets. Partialagonists are defined as compounds that have reduced efficacy forinducing conformational change in receptors (typically 40-80%) relativeto full agonists, and which may induce agonist effects at low dose butantagonist effects at high dose.

Relatively few studies have investigated glutamate- or NMDAR-relatedmeasures in depression. To the extent that it has been studied, it hasbeen suggested that depression is associated with reduced NMDAR function(e.g. Frye et al., 2007). Sumiyoshi et al. (2004) found to no differencein plasma glycine levels relative to controls. In contrast, otherstudies have linked high glycine levels to poor response to SSRIs,possibly in association with abnormalities in the glycine hydroxylase(decarboxylating) (aka decarboxylase, GLDC) gene suggesting thattreatment refractory depression may constitute an etiologically distinctform of the disorder (Ji et al., 2011). Depression may be modeled inrodents using assays such as learned helplessness, forced swim or tailsuspension tests. There are at present no animal models specificallysensitive to treatment refractory depression. Elevated glycine levelsare also reported in relapsing mania. For example, Hoekstra et al., 2006reported mean plasma levels of 283.3±102.7 for manic patients vs. a meanof 224.0±51.5 for controls (p=0.02).

Recently, the non-competitive NMDAR antagonist ketamine has also beenshown to have antidepressant effects in humans when tested inindividuals with treatment-resistant depression. The compound showssimilar effects in both unipolar and bipolar depression. Othernon-competitive NMDAR antagonists such as MK-801 also showanti-depressant effects in animal models. However, antidepressanteffects induced by ketamine are associated with exacerbation ofpsychosis, which greatly reduces their utility in clinical situations.

A recent, double-blind, randomized, placebo-controlled clinical trialevaluating the NMDAR-2B subunit-selective antagonist CP-101,606 foundthat this agent also induced significant and relatively rapidantidepressant effects in patients with treatment-resistant MDD. As withketamine, however, CP-101,606 was used by intermittent IV infusion,limiting its clinical utility. Moreover, as with ketamine, significantdissociative effects emerged during CP-101,6060 infusion. Other NMDARantagonists, such as memantine, have not shown beneficial clinicalresults. Based upon the lack of efficacy of memantine, it has beensuggested that intravenous infusion may be critical for effectanti-depressive treatment.

D-cycloserine is a compound currently approved for treatment oftuberculosis (TB). Psychotropic effects of cycloserine were noted in thelate 1950's in patients being treated for TB. In an initial report,effects of cycloserine were noted on symptoms such as anorexia, astheniaand insominia. However, no formal psychiatric diagnoses were made.Furthermore, cycloserine was recommended primarily for treatments oftension and insomnia, as opposed to depression.

Formal further studies with D-cycloserine were not pursued until the1980's when it was observed that D-cycloserine functions as a partialagonist (mixed agonist/antagonist) at the glycine binding site of theNMDAR, with agonist effects predominating at low dose and antagonisteffects predominating at high dose. As compared to glycine,D-cycloserine shows approximately 50% efficacy in stimulating NMDAreceptors when used at maximal concentration.

Because of its ability to bind to NMDAR and because of theories linkingNMDAR to schizophrenia, D-cycloserine has been studied in treatmentresistant schizophrenia. At low doses, D-cycloserine has been found toproduce beneficial effects in some but not all studies, and mayexacerbate symptoms in individuals receiving clozapine. Furthermore, athigher doses (>250 mg), however, D-cycloserine exacerbates psychosis andso according to package label insert is contra-indicated inschizophrenia, depression and anxiety disorders.

D-cycloserine has also been assessed in the treatment of anxietydisorders, PTSD and enhancement of learning and memory at doses of50-500 mg, with the goal primarily of enhancing NMDAR function. Inaddition, use of D-cycloserine has been claimed for enhancement ofcognition at doses of up to 100 mg and for treatment of a wide varietyof neuropsychiatric disorders at doses of up to 500 mg. It has also beentaught that D-cycloserine may be useful in augmenting cognition inParkinsons disease.

In both anxiety and schizophrenia studies, it has been noted thateffects of D-cycloserine may decrease over time during repeatedtreatment, leading some to advocate use of weekly, rather than daily,D-cycloserine. When used as augmentation of behavior therapy foranxiety, D-cycloserine is used episodically in combination withbehavioral therapy sessions.

Research with D-cycloserine in preclinical models has also not suggestedits usefulness at high dose in treatment of depression. Partial agonistsof NMDAR, in particular 1-aminocyclopropanecarboxylic acid (ACPC) havebeen reported to have efficacy in animal models, but have not yet beentested in human studies. When used in these models, D-cycloserine wasnoted to have inconsistent effects and to be less effective than eitherACPC or imipramine. Furthermore, effects were only observed at thelowest dose tested, arguing away from high dose treatment in humans. Inanimal depression models, tolerance over weeks has also been observed,arguing against sustained long term use.

D-cycloserine reported for use at a dose of 250 mg/day was found to bewithout significant effect on symptoms of major depression and moreover,commonly available prescribing information states that cycloserine useis contraindicated in individuals with a history of epilepsy,depression, severe anxiety, or psychosis (Lilly. Seromycin (cycloserine)capsules prescribing information. Indianapolis, Ind.; 2005 Apr. 28).

SUMMARY OF THE INVENTION

In one embodiment, this invention provides an oral dosage regimenconsisting essentially of two active ingredients, wherein a first ofsaid two active ingredients is D-cycloserine at a dosage of from about500 mg/day-1200 mg/day and wherein a second of said two activeingredients is a therapeutic agent for the treatment of depression, forreduction of the incidence of suicide or for the treatment of suicideideation in a subject or population, or a combination thereof.

In some embodiments, the second therapeutic agent comprises atetracyclic antidepressant (TeCA), selective serotonin reuptakeinhibitor (SSRI), a serotonin/norephinephrine reuptake inhibitor (SNRI)or a combination thereof.

In some embodiments, the second therapeutic agent is an antipsychoticagent, which antipsychotic agent is also approved for the treatment ofdepression

In some embodiments, the antipsychotic agent is selected from the groupconsisting of quetiapine, risperidone, olanzapine and aripiprazole

In some embodiments, the second therapeutic agent is provided at asubtherapeutic dose, if the second therapeutic agent were providedalone.

In some embodiments, the two active ingredients are provided in a singlepharmaceutical composition.

In some embodiments, this invention provides a method for treatingdepression in a subject in need thereof, said method comprisingproviding said subject with an oral dosage regimen as herein described.

In some embodiments, the subject has previously received treatment withan anti-depressant agent.

In some embodiments, the said anti-depressant agent is ketamine. In someembodiments, the anti-depressant agent is an anti-NMDA agent.

In some embodiments, the patients have pretreatment plasma levels ≧300μM glycine. In some embodiments, the subject possesses a polymorphismfor a GLDC allele. In some embodiments, the subject possesses apolymorphism at locus rs10975641, rs11789777, rs10975734, rs1658957,rs11612037, rs7485577, rs2988418, rs1755615 or rs12004478 of the GLDCgene.

In some embodiments, the subject suffers from mania, or in someembodiments, the subject suffers from bipolar disorder. In someembodiments, the invention provides a method for reducing the incidenceor treating suicide or suicide ideation in a subject or population inneed thereof, the method comprising providing the subject with an oraldosage regimen as herein described.

In some embodiments, the invention provides an oral dosage regimen forthe treatment of depression, said dosage regimen comprising:

-   -   a first dosage of 50-300 mg/day of D-cycloserine for from 1 to 5        days, followed by:    -   a second dosage of 300-600 mg/day of D-cycloserine for from 5 to        20 days, followed by:    -   a third dosage of from 600-800 mg/day of D-cycloserine for from        21 days to 28 days, followed by:    -   a fourth dosage of from 800-1200 mg/day of D-cycloserine for        from day 29-43.

In some embodiments, the invention provides a pharmaceuticallyacceptable medication dispensing package containing multiple dosageunits of medicaments comprising an oral dosage regimen of D-cycloserinefor the treatment of depression, in a manner that provides a complexregimen of said medicaments for consumption by a patient over the periodof time necessary to treat depression in a subject, said packageincluding first pills comprising 50-300 mg/day of D-cycloserine to beadministered for from 1 to 5 days, followed by second pills comprising300-600 mg/day of D-cycloserine to be administered for from 5 to 20days, followed by third pills comprising from 600-800 mg/day ofD-cycloserine to be administered for from 21 days to 28 days, followedby fourth pills comprising 800-1200 mg/day of D-cycloserine for from day29-43 days,

wherein the package retains and presents said medicaments at separatelocations identified by visibly discernible indicia identifying theadministration schedule for the medicaments contained respectively,therein.

In some embodiments, the invention provides a method for treatingdepression in a subject, said method comprising orally administeringD-cycloserine to a subject, wherein said D-cycloserine is administeredin a dosage regimen as follows:

-   -   a first dosage of 50-300 mg/day of D-cycloserine for from 1 to 5        days, followed by:    -   a second dosage of 300-600 mg/day of D-cycloserine for from 5 to        20 days, followed by:    -   a third dosage of from 600-800 mg/day of D-cycloserine for from        21 days to 28 days, followed by:    -   a fourth dosage of from 800-1200 mg/day of D-cycloserine for        from day 29-43.

In some embodiments, the invention provides for the use of D-cycloserinein the preparation of a medicament or kit, formulated to provide adosage regimen as follows

-   -   a first dosage of 50-300 mg/day of D-cycloserine for from 1 to 5        days, followed by:    -   a second dosage of 300-600 mg/day of D-cycloserine for from 5 to        20 days, followed by:    -   a third dosage of from 600-800 mg/day of D-cycloserine for from        21 days to 28 days, followed by:    -   a fourth dosage of from 800-1200 mg/day of D-cycloserine for        from 29 days to 43 days; for treating depression in a subject,        wherein said D-cycloserine is formulated for oral administration        to a subject.

In some embodiments, the invention provides a pharmaceutical compositioncomprising D-cycloserine formulated for oral administration providing adosage of 1000 mg/day. In some embodiments, the invention provides apharmaceutical composition comprising D-cycloserine formulated for oraladministration providing a dosage of between 775-2000 mg/day.

In some embodiments, the invention provides a method for the treatmentof depression in a subject, said method comprising orally administering1000 mg/day of D-cycloserine to a subject in need thereof, wherein saidsubject has first been administered D-cycloserine at dosage of between50-500 mg/day of D-cycloserine for from 7 days to 21 says prior toadministering said 1000 mg/day or D-cycloserine. In some embodiments,the invention provides a method for the treatment of depression in asubject, said method comprising orally administering between 775-2000mg/day of D-cycloserine to a subject in need thereof, wherein saidsubject has first been administered D-cycloserine at dosage of between50-500 mg/day of D-cycloserine for from 7 days to 21 says prior toadministering said 775-2000 mg/day or D-cycloserine.:

In other embodiments, the invention provides for the use ofD-cycloserine in the preparation of a medicament formulated for oraladministration at a dosage of 1000 mg/day for the treatment ofdepression in a subject in need thereof. In other embodiments, theinvention provides for the use of D-cycloserine in the preparation of amedicament formulated for oral administration at a dosage of 775-2000mg/day for the treatment of depression in a subject in need thereof.

In other embodiments, the invention provides a method for treatingneuropsychiatric disorders associated with elevated plasma glycinelevels is a subject, said method comprising the step of administering anNMDAR glycine-site antagonist to said subject. In some embodiments, thesubject suffers from treatment-refractory depression or relapsing maniaand in some embodiments, the subject exhibits a pretreatment plasmalevel of >300 μM glycine.

In some embodiments, the invention provides a method for reducing theincidence or treating suicide or suicide ideation in a subject orpopulation, said method comprising orally administering D-cycloserine toa subject, wherein said D-cycloserine is administered in a dosageregimen as follows

-   -   a first dosage of 50-300 mg/day of D-cycloserine for from 1 to 5        days, followed by:    -   a second dosage of 300-600 mg/day of D-cycloserine for from 5 to        20 days, followed by:    -   a third dosage of from 600-800 mg/day of D-cycloserine for from        21 days to 28 days, followed by:    -   a fourth dosage of from 800-1200 mg/day of D-cycloserine for        from 29 days to 43 days.

In some embodiments, the invention provides for the use of D-cycloserinefor the preparation of a medicament/kit formulated to provide a dosageregimen as follows

-   -   a first dosage of 50-300 mg/day of D-cycloserine for from 1 to 5        days, followed by:    -   a second dosage of 300-600 mg/day of D-cycloserine for from 5 to        20 days, followed by:    -   a third dosage of from 600-800 mg/day of D-cycloserine for from        21 days to 28 days, followed by:    -   a fourth dosage of from 800-1200 mg/day of D-cycloserine for        from 29 days to 43 days.        for reducing the incidence or treating suicide or suicide        ideation in a subject or population, wherein said D-cycloserine        is formulated for oral administration.

DETAILED DESCRIPTION OF THE INVENTION

This invention provides, in some embodiments, oral dosage regimens,which are useful in the treatment of depression in a subject in needthereof, or in the reduction of the incidence or treatment of suicide orsuicide ideation in a subject or population in need thereof.

In some embodiments, the invention provides an oral dosage regimenconsisting essentially of two active ingredients, wherein a first ofsaid two active ingredients is D-cycloserine at a dosage of from about500 mg/day-1200 mg/day and wherein a second of said two activeingredients is a therapeutic agent for the treatment of depression, forreduction of the incidence of suicide or for the treatment of suicideideation in a subject or population, or a combination thereof.

In some embodiments, the second therapeutic agent comprises atetracyclic antidepressant (TeCA), selective serotonin reuptakeinhibitor (SSRI), a serotonin/norephinephrine reuptake inhibitor (SNRI)or a combination thereof.

In some embodiments, the second therapeutic agent is an antipsychoticagent, which antipsychotic agent is also approved for the treatment ofdepression

In some embodiments, the antipsychotic agent is selected from the groupconsisting of to quetiapine, risperidone, olanzapine and aripiprazole

In some embodiments, the two active ingredients are provided in a singlepharmaceutical composition, and in some embodiments, the inventioncontemplates a kit or combined dispenser packet containing each of thetwo active ingredients.

It is to be understood that the invention contemplates theco-administration of either of the two active ingredients to a subject,whether such administration is combined in a single formulation or inseparate formulations and whether such administration is coincident orstaggered.

In some embodiments, this invention provides a method for treatingdepression in a subject in need thereof, said method comprisingproviding said subject with an oral dosage regimen as herein described.

In some embodiments, the subject suffers from mania, or in someembodiments, the subject suffers from bipolar disorder. In someembodiments, the invention provides a method for reducing the incidenceor treating suicide or suicide ideation in a subject or population inneed thereof, the method comprising providing the subject with an oraldosage regimen as herein described.

This invention provides, in some embodiments, for staggered dosageregimens, medication dispensing packages for providing the same andmethods of use thereof for the treatment of depression in a subject,whereby a dosage of up to 2000 mg/of D-cycloserine is safely provided toa subject resulting in effective treatment of depression and the withoutpromoting psychosis in the subject.

In one embodiment, this invention provides an oral dosage regimen forthe treatment of depression, said dosage regimen comprising:

-   -   a first dosage of 50-300 mg/day of D-cycloserine for from 1 to 5        days, followed by:    -   a second dosage of 300-600 mg/day of D-cycloserine for from 5 to        20 days, followed by:    -   a third dosage of from 600-800 mg/day of D-cycloserine for from        21 days to 28 days, followed by:    -   a fourth dosage of from 800-1200 mg/day of D-cycloserine for        from 29 days to 43 days.

In some embodiments, the first dosage comprises 250 mg/day ofD-cycloserine for 3 days, in some embodiments, the second dosagecomprises 500 mg/day of D-cycloserine for 18 days, in some embodiments,the third dosage comprises 750 mg/day of D-cycloserine for 7 days, insome embodiments, the fourth dosage comprises 1000 mg/day ofD-cycloserine for 18 days and in some embodiments, the inventionprovides for the administration of the combined dosage regimen accordingto this aspect. In some embodiments, the fourth dosage comprises between775-2000 mg/day of D-cycloserine

In some embodiments, the first dosage comprises 250 mg/day ofD-cycloserine from day 0-7, in some embodiments, the second dosagecomprises 500 mg/day of D-cycloserine from day 12-20, in someembodiments, the third dosage comprises 750 mg/day of D-cycloserine fromday 18-25 days, in some embodiments, the fourth dosage comprises 1000mg/day of D-cycloserine from day 25-35 days and in some embodiments, theinvention provides for the administration of the combined dosage regimenaccording to this aspect. In some embodiments, the fourth dosagecomprises between 775-2000 mg/day of D-cycloserine from day 30-40. Insome embodiments, the first dosage comprises 250 mg/day of D-cycloserinefrom day 0-7, or any number of days from within such range, such as, forexample, days 1-3, 1-4, 1-5, etc. In some embodiments, the second dosagecomprises 500 mg/day of D-cycloserine from day 4-21, or any number ofdays from within such range, such as, for example, days 4-16, 5-21,7-21, etc. In some embodiments, the third dosage comprises 750 mg/day ofD-cycloserine from day 20-35 days, or any number of days from withinsuch range, such as, for example, days 22-28, 21-30, 22-35, etc. In someembodiments, the fourth dosage comprises 1000 mg/day of D-cycloserinefrom day 36-50 days or any number of days from within such range, suchas, for example, days 29-42, 33-50, 31-45, etc. In some embodiments, theinvention provides for the administration of the combined dosage regimenaccording to this aspect.

Surprisingly, the Inventors have found herein that higher dosages ofD-cycloserine can be significantly well tolerated, treating depressionwithout any signs of developing psychosis in the subject, whenD-cycloserine is combined with an antidepressant agent, especially whenthe dosage treatment schedule is increased over time in a relativelyslow and fixed manner. Furthermore, the combination of D-cycloserineplus an anti-depressant is more effective than treatment withanti-depressant alone.

In some embodiments, the dosage regimens herein described provide for atherapeutically effective amount of D-cycloserine, in accordance withthe regimens as herein described, providing an effective therapy fordepression.

In some embodiments, reference to an “effective” amount or a“therapeutically effective amount” of D-cycloserine or other therapeuticagents referenced herein, it is meant a nontoxic but sufficient amountof the same to provide the desired effect. In a combination therapy ofthe present invention, an “effective amount” of one component of thecombination is to the amount of that compound that is effective toprovide the desired effect when used in combination with the othercomponents of the combination. The amount that is “effective” will varyfrom subject to subject, depending on the age and general condition ofthe individual, the particular active agent or agents, and the like.Thus, it is not always possible to specify an exact “effective amount.”However, an appropriate “effective” amount in any individual case may bedetermined by one of ordinary skill in the art using routineexperimentation

The terms “treating” and “treatment” as used herein refer to reductionin severity and/or frequency of symptoms, elimination of symptoms and/orunderlying cause, prevention of the occurrence of symptoms and/or theirunderlying cause, and improvement or remediation of damage. Thus, forexample, “treating” a patient involves prevention of a particulardisorder or adverse physiological event in a susceptible individual aswell as treatment of a clinically symptomatic individual.

D-cycloserine, or DCS, refers to the chemical D-cycloserine (CA IndexName: 3-Isoxazolidinone, 4-amino-, (4R)-(9CI); CAS Registry No.68-41-7), or pharmaceutically acceptable salts thereof. DCS is an FDA(United States Food and Drug Administration)-approved drug for treatmentof tuberculosis, and is sold by Eli Lilly and Company under the tradename Seromycin®. DCS is a structural analog of D-alanine, and is abroad-spectrum antibiotic produced by some strains of Streptomycesorchidaceus and S. garphalus.

Indicia is provided and disposed adjacent the columns and rows fordisplaying common days and successive weeks. Thus, the package providesfor a titration schedule which prevents adverse events as a result ofmis-dosing. As a result, the package in accordance with the presentinvention provides for a safer and accordingly more beneficial methodfor enabling compliance with the regimen.

In some embodiments, the invention provides a regimen further comprisingadministering a second therapeutic agent for the treatment of depressionor for the reduction of the incidence or treatment of suicide or suicideideation in a subject or population in need thereof.

In some embodiments, the second therapeutic agent comprises atetracyclic antidepressant (TeCA), selective serotonin reuptakeinhibitor (SSRI), a serotonin/norephinephrine reuptake inhibitor (SNRI),an antipsychotic approved for treatment of depression or a combinationthereof.

In some embodiments, the second therapeutic agent may comprise any agentas described and/or exemplified herein, for example, the secondtherapeutic agent may comprise antidepresseants, such as monoamineoxidase inhibitors (MAOI), TCAs such as, but not limited to imipramine,amitryptiline, desipramine, clomipramine, TeCAs such as mianserin,mirtazapine, serotonin (SSRI) and serotonin/norephinephrine (SNRI)reuptake inhibitors, such as fluoxetine, fluvoxamine, paroxetine,citalopram, escitalopram, duloxetine, venlafaxine and others, as will beappreciated by the skilled artisan.

In some embodiments, the regimen comprises administering a secondtherapeutic agent which is an anti-depressant, and said dosage is inaccordance with standard prescribing guidelines.

In some embodiments, the regimen comprises a second therapeutic agentwhich is a psychotropic medication.

In some embodiments, the regimen comprises a second therapeutic agentwhich is venlafaxine, and in some embodiments, the venlafaxine is at adosage of 25-500 mg.

In some embodiments, the regimen comprises a second therapeutic agentwhich is quetiapine, and in some embodiments, the quetiapin is at adosage of 50-1000 mg.

In some embodiments, the regimen comprises D-cycloserine at a dosage ofbetween 500-1200 mg and an antidepressant as herein described, wheresuch regimen is particularly suitable for a patient previously receivingD-cyloserine alone at a dosage of less than 250 mg.

In some embodiments, the regimen includes a second therapeutic agent,which is an anti-anxiolytic, or a mood stabilizer.

In some embodiments, the anti-anxiolytic includes, inter alia, SSRI's,Atarax, Benadryl, azaspirones, benzodiazepines, such as Ativan, Centrax,Dalmane, Klonopin, Librium, Paxipam, Restoril, Serax, Tranxene, Valium,Xanax, beta blockers, such as Inderal, Tenormin and others as will beappreciated by the skilled artisan.

In some embodiments, the mood stabilizers may comprise lithium, valproicacid, carbamazepine, Eskalith, Lithium Carbonate, Lithonate, Depakote,Divalproex Sodium, Gabatril, Tiagabine, Zyprexa, Olanzapine and others,as will be appreciated by the skilled artisan.

In some embodiments, the regimen comprises administering a secondtherapeutic agent at a dosage which is considered to be suboptimal fortreating depression in said subject when treating said subject with saidsecond therapeutic agent alone. In some embodiments, such administrationof the second therapeutic agent may be titrated downward, for example,as the dosage of D-cycloserine is increased in a subject, the dosage ofthe second therapeutic agent can be diminished gradually, over time. Inanother embodiment, the invention contemplates reaching maximaltreatment levels of both D-cycloserine initially followed by gradualreduction of the second therapeutic agent.

In some embodiments, the invention provides a pharmaceuticallyacceptable medication dispensing package containing multiple dosageunits of medicaments comprising an oral dosage regimen of D-cycloserinefor the treatment of depression, in a manner that provides a complexregimen of said medicaments for consumption by a patient over the periodof time necessary to treat depression in a subject, said packageincluding first pills, capsules or other oral dosage forms comprising50-300 mg/day of D-cycloserine to be administered for from 1 to 5 days,followed by second pills, capsules or other oral dosage forms comprising300-600 mg/day of D-cycloserine to be administered for from 5 to 20days, followed by third pills, capsules or other oral dosage formscomprising from 600-800 mg/day of D-cycloserine to be administered forfrom 21 days to 28 days, followed by fourth pills, capsules or otheroral dosage forms comprising 800-1200 mg/day of D-cycloserine for fromday 29-43 days, wherein the package retains and presents saidmedicaments at separate locations identified by visibly discernibleindicia identifying the administration schedule for the medicamentscontained respectively, therein.

In some embodiments, the pharmaceutically acceptable medicationdispensing package specifically contains first pills, capsules or otheroral dosage forms comprising a dosage of 250 mg/day of D-cycloserine. Insome embodiments, the pharmaceutically acceptable medication dispensingpackage specifically contains second pills, capsules or other oraldosage forms comprising a dosage of 500 mg/day of D-cycloserine for 18days. In some embodiments, the pharmaceutically acceptable medicationdispensing package specifically contains third pills, capsules or otheroral dosage forms comprising a dosage of 750 mg/day of D-cycloserine for7 days. In some embodiments, the pharmaceutically acceptable medicationdispensing package specifically contains fourth pills, capsules or otheroral dosage forms comprising a dosage of 1000 mg/day of D-cycloserinefor 18 days. In some embodiments, the pharmaceutically acceptablemedication dispensing package specifically contains first, second, thirdand fourth pills as described according to this aspect.

In some embodiments, the pharmaceutically acceptable medicationdispensing package is a blister pack, containing multiple discretelylocalized pills, capsules or other oral dosage forms, which differ intheir content by desired groupings, for example, wherein the firstpills, capsules or other oral dosage forms are in a part of a first rowor a single row, or a row and an additional portion of a subsequent row,and contain a particular indicia, and the second pills, capsules orother oral dosage forms are grouped in a part of a subsequent row orwithin such row, or a row and an additional portion of a subsequent row,and contain a particular indicia, and to so forth, for each of thedosage forms contemplated.

In some embodiments, the pharmaceutically acceptable medicationdispensing package is disposable.

In some embodiments, the pharmaceutically acceptable medicationdispensing package comprises a second therapeutic agent for thetreatment of depression retained and presented within a separatelocation in said package, and said second therapeutic agent isidentified by visibly discernible indicia distinguishing the same fromsaid first, second, third and fourth pills. Such second therapeuticagent may be any as described herein, and as will be appreciated by theskilled artisan.

In some embodiments, the pharmaceutically acceptable medicationdispensing package comprises a second therapeutic agent at a dosagewhich is considered to be suboptimal for treating depression in saidsubject when treating said subject with said second therapeutic agentalone, as described hereinabove.

In some embodiments of the present invention, different sets of tablets,capsules or other oral dosage forms are disposed in different rows witheach row being indicated by a successive week and each column beingindicated as a different day of the week. In this embodiment, the setsof tablets having increased doses are disposed in receivers in rowsindicated as successive dosage changes.

It will be appreciated that the formal disposition of the differentdosages within the medication dispensing package may be according to anyplan or pattern, for example, the dosage forms may be disposed indifferent columns, with each column or successive part thereof beingindicated as a successive dosage, while each row, for example, mayindicate a particular day of the week.

In another embodiment of the present invention, the medicationdispensing package for enabling compliance with a regimen of changingdoses of medication over a period of time includes a backing having anarray or receivers with the array including a plurality of columns and aplurality of rows. In this embodiment, a plurality of sets of tabletsare provided with each set being disposed in receivers of a plurality ofadjacent rows or a plurality of adjacent columns. This plurality may betwo and each tablet in a set has a common dose of medication and adifferent dose than a tablet or other oral dosage form in a differentset.

In some embodiments, according to this aspect, pairs of adjacent rowsmay have differing sets of oral dosage forms, for example, allowing forthe change of dosage over a several-week period of time from the variousdosages or ranges of dosages presented herein.

In some embodiments, the pharmaceutical compositions can be administeredto the to patient by any, or a combination, of several routes, forexample, whereas D-cycloserine may be administered orally, the secondtherapeutic agent administered, as herein described may be administeredby any appropriate route, for example, such second therapeutic agent maybe provided as an oral, intravenous, trans-mucosal (e.g. nasal, vaginal,etc.), pulmonary, transdermal, ocular, buccal, sublingual,intraperitoneal, intrathecal, intramuscular, or long term depotpreparation.

In some embodiments, this invention contemplates compositions containingboth D-cycloserine and a at a therapeutic agent for the treatment ofdepression, suicide or suicide ideation in a subject, where thecomposition is formulated to provide an oral daily dosage of from about500 mg/day-1200 mg/day

In some embodiments, solid compositions for oral administration cancontain suitable carriers or excipients, such as corn starch, gelatin,lactose, acacia, sucrose, microcrystalline cellulose, kaolin, mannitol,dicalcium phosphate, calcium carbonate, sodium chloride, lipids, alginicacid, or ingredients for controlled slow release. Disintegrators thatcan be used include, without limitation, micro-crystalline cellulose,corn starch, sodium starch glycolate and alginic acid. Tablet bindersthat may be used include, without limitation, acacia, methylcellulose,sodium carboxymethylcellulose, polyvinylpyrrolidone (Povidone),hydroxypropyl methylcellulose, sucrose, starch, and ethylcellulose.

In some embodiments, liquid compositions for oral administrationprepared in water or other aqueous vehicles can include solutions,emulsions, syrups, and elixirs containing, together with the activecompound(s), wetting agents, sweeteners, coloring agents, and flavoringagents. Various liquid and powder compositions can be prepared byconventional methods for inhalation into the lungs of the patient to betreated.

In some embodiments, the second therapeutic agent may be formulated asan injectable composition, which may contain various carriers such asvegetable oils, dimethylacetamide, dimethylformamide, ethyl lactate,ethyl carbonate, isopropyl myristate, ethanol, polyols (glycerol,propylene glycol, liquid polyethylene glycol, and the like).

In some embodiments, the second therapeutic agent may be formulated asan intravenous injection, the compounds may be administered by the dripmethod, whereby a pharmaceutical composition containing the activecompound(s) and a physiologically acceptable excipient is infused.

Physiologically acceptable excipients may include, for example, 5%dextrose, to 0.9% saline, Ringer's solution or other suitableexcipients. For intramuscular preparations, a sterile composition of asuitable soluble salt form of the compound can be dissolved andadministered in a pharmaceutical excipient such as Water-for-Injection,0.9% saline, or 5% glucose solution, or depot forms of the compounds(e.g., decanoate, palmitate, undecylenic, enanthate) can be dissolved insesame oil. Alternatively, the pharmaceutical composition can beformulated as a chewing gum, lollipop, or the like.

While the dosage regimen and methods described herein represent anoptimum arrived at by administering the D-cycloserine orally, it will beappreciated by the skilled artisan that a lower dosage may beaccomplished with the same by administering the D-cycloserine by a routethat does not undergo first pass metabolism. According to this aspect,the dosage can be adjusted to be staggered accordingly, as presented forthe oral dosage regimens described herein, with proportionately lowerdosages, to accommodate a non-oral administration route, and suchalterations are to be considered to be an embodied regimen of thisinvention.

In other embodiments, the formulations as herein described, inparticular with regard to oral formulations, are envisioned to compriseslow release tablet formulations. Such slow release tablet formulationsmay, for example, comprise commercially available formulationscontaining known anti-depressant medications, such as, for example,Effexor® or Seroquel®, both of which are already available in extendedlength (XR) formulations, however the formulation may be modified tofurther incorporate D-cycloserine.

In other embodiments, the formulations as herein described, inparticular with regard to oral formulations, are envisioned to compriseboth short acting and extended release formulations. Extended releaseformulations have the advantage inter alia of minimizing the differencebetween peak and trough levels of drug, and thereby to increaseeffectiveness and/or reduce side effects of a medication.

Methods for the formulation of the described regimens herein are wellknown, and the skilled artisan will appreciate that it isstraightforward to prepare the oral dosage regimens as herein described.Applicants, for example, refer to Gibaldi's Drug Delivery Systems inPharmaceutical Care, Desai A & Lee M (eds), Bethesda, Md.: AmericanSociety of Health-System Pharmacists, 2007.

D-cycloserine has a relatively short half-life in man, and therefore ispresently used in BID dosing. In some embodiments of the invention BIDdosing is envisioned. According to this aspect, and in some embodiments,such consideration will nonetheless ensure that the daily dosagedescribed for the regimens defined herein are not exceeded.

In some embodiments of the invention, D-cycloserine is microencapsulatedto increase its circulating half-life. According to this aspect, and insome embodiments, the microencapsulated compound would then be combinedeither with a anti-depressant medication that is already administeredonce daily (e.g. sertraline, citalopram, aripiprazole) to insure thatcycloserine cannot be taken without accompanying antidepressant (whichwould increase risk of CNS side effects). Alternatively, the drug couldbe combined with an anti-depressant compound that is already typicallygiven in divided doses (e.g. venlafaxine, quetiapine) and the two drugscould then be microencapsulated in common to yield a once-dailyformulation with similar half-life between the two ingredients.Microencapsulation using standard approaches for (cf. Doshi DH, OralDrug Delivery Systems, in Gibaldi's Drug Delivery Systems inPharmaceutical Care, Desai A & Lee M (eds), Bethesda, Md.: AmericanSociety of Health-System Pharmacists, 2007. pp. 23-43) such as use ofcoating materials or matrix-based oral delivery systems. In oneapproach, for example, drugs are mixed with a gelling agent, such ashydroxypropylmethylcellulose or hydroxylpropylcellulose, which form ahydrophilic matrix (gel) upon contact with water that delays release ofthe compound. Release properties can be regulated by selection ofspecific gelling agents, as is known in the art (see, for example, U.S.Pat. No. 5,948,437; European patent EP20040765928, U.S. Pat. No.7,807,195).

Other compounds that can be used to control release include cellulose,ethylcellulose, gelatin, hypromellose, iron oxide and titanium oxide. Insome matrix systems, drug release is controlled mainly by diffusionthrough matrix pores and not by the erosion of the polymers. Drugdelivery can also be controlled by use of reservoir type systems inwhich release is controlled by osmotic gradient across the coatingmembrane. Capsules can be manufactured which contain granules withdifferent microencapsulation properties which can be blended to achievea composition that has a desired release rate.

In one embodiment of the invention, D-cycloserine is microencapsulatedalong with quetiapine or a pharmaceutically acceptable salt thereofusing a gelling agent such as hydroxypropyl methylcellulose, togetherwith one or more pharmaceutically acceptable excipients. In someembodiments, the sustained release formulation comprises a hydrophilicmatrix comprising a gelling agent, preferably hydroxypropylmethylcellulose, D-cycloserine, quetiapine and pharmaceuticallyacceptable salts thereof, together with one or more pharmaceuticallyacceptable excipients.

In another embodiment of the invention, D-cycloserine would be combinedwith venlafaxine formulated for extended release capsules (see patent EP0797991, fully incorporated to herein by reference). In this embodiment,D-cycloserine and venlafaxine would be formulated to produce an extendedrelease formulation by addition of hydroxypropylmethylcellulose toproduce spheroids containing the active ingredients D-cycloserine andvenlafaxine and then costed with a film coating to further delay releaseand/or extend the release profile. Concentrations of active ingredients,HPMC, film coatings and other excipients could be adjusted to producethe desired extended relief profile. For example, spheroids couldcontain from about 0.3-0.6% HPMC and coating levels could contain fromabout 6-8% film coating. Microcrystalline cellulose may be used insteadof HPMC as described in EP 0797991, fully incorporated herein byreference.

In another embodiment of the invention, D-cycloserine would be combinedwith venlafaxine formulated for extended release tablets (see patentEP20040765928, fully incorporated herein by reference). In suchembodiment, coboxyvinyl polymer is used as agent for formulation oftablets along with D-cycloserine and venlafaxine, with caboxyvinylcomprising about 8%-about 40% w/w of the tablet, most preferably fromabout 10-20%. Other rate controlling excipients for example hydrophilicmatrices such as HPMC or hydrophobic matrices such as ethyl cellulose,waxes or fats, may be used in conjunction with carboxy vinyl polymer, inwhich case the amount of carboxy vinyl polymer may be reduced from thevalues above. A functional coating, for example an enteric coat or delaycoat, may be applied to the tablet to delay and/or extend the releaseprofile of the active D-cycloserine and anti-depressant ingredients.Carboxyvinyl polymers and coating agents are commercially available withpreferential utility of Eudragit RS30D, Eudragit RL30D and Carbopol 971P(B.F. Goodrich, Cleveland, Ohio) as described in EP20040765928, fullyincorporated herein by reference.

For delayed release formulation, ideal choice, concentration andcomposition of gelling agent, functional coatings or other ingredientcan be determined by use of simulated gastrointestinal fluids to producea formulation with prolonged release of D-cycloserine and secondanti-depressant agent such as venlafaxine or quetiapine to produce aformulation with an extended relief profile of >8 hr, preferably 8-24hr.

In some embodiments, the invention provides a method for treatingdepression in a subject, said method comprising orally administeringD-cycloserine to a subject, wherein said D-cycloserine is administeredin a dosage regimen as follows

-   -   a first dosage of 50-300 mg/day of D-cycloserine for from 1 to 5        days, followed by:    -   a second dosage of 300-600 mg/day of D-cycloserine for from 5 to        20 days, followed by:    -   a third dosage of from 600-800 mg/day of D-cycloserine for from        21 days to 28 days, followed by:    -   a fourth dosage of from 800-1200 mg/day of D-cycloserine for        from day 29-43.

In some embodiments, the invention provides for the use of D-cycloserinein the preparation of a medicament or kit, formulated to provide adosage regimen as follows

-   -   a first dosage of 50-300 mg/day of D-cycloserine for from 1 to 5        days, followed by:    -   a second dosage of 300-600 mg/day of D-cycloserine for from 5 to        20 days, followed by:    -   a third dosage of from 600-800 mg/day of D-cycloserine for from        21 days to 28 days, followed by:    -   a fourth dosage of from 800-1200 mg/day of D-cycloserine for        from day 29-43; for treating depression in a subject, wherein        said D-cycloserine is formulated for oral administration to a        subject.

In some embodiments, according to this aspect, the first dosagecomprises 250 mg/day of D-cycloserine for 3 days, and in someembodiments, the second dosage comprises 500 mg/day of D-cycloserine for18 days and in some embodiments, the third dosage comprises 750 mg/dayof D-cycloserine for 7 days and in some embodiments, the fourth dosagecomprises 1000 mg/day of D-cycloserine for 18 days, and in someembodiments, the first, second, third and fourth dosage comprise thatdescribed in accordance with this aspect.

In some embodiments, the method further comprises administering a secondtherapeutic agent for the treatment of depression to said subject. Insome embodiments, the medicaments in accordance with the described usesof this invention further comprises a second therapeutic agent for thetreatment of depression in said subject.

According to this aspect, the method is not limited in terms of thetiming of the administration of the second therapeutic agent, such thatthe methods of this invention contemplate a subject already treated witha second therapeutic agent, or a naïve subject concomitantly treatedwith D-cycloserine and the second therapeutic agent, or in someembodiments, the subject initially treated with D-cycloserine is thenadministered a second therapeutic agent, and each of these scenariosrepresents an embodiment of this invention. Such second therapeuticagent will be any such agent as herein described, including atetracyclic antidepressant (TeCA), selective serotonin reuptakeinhibitor (SSRI), a serotonin/norephinephrine reuptake inhibitor (SNRI),an antipsychotic approved for treatment of depression or a combinationthereof.

In some embodiments, in accordance with the methods/uses of thisinvention, the regimen comprises administering a second therapeuticagent at a dosage which is considered to to be suboptimal for treatingdepression in said subject when treating said subject with said secondtherapeutic agent alone.

In some embodiments, the invention provides a method for reducing theincidence or treating suicide or suicide ideation in a subject orpopulation, said method comprising orally administering D-cycloserine toa subject, wherein said D-cycloserine is administered in a dosageregimen as follows

-   -   a first dosage of 50-300 mg/day of D-cycloserine for from 1 to 5        days, followed by:    -   a second dosage of 300-600 mg/day of D-cycloserine for from 5 to        20 days, followed by:    -   a third dosage of from 600-800 mg/day of D-cycloserine for from        21 days to 28 days, followed by:    -   a fourth dosage of from 800-1200 mg/day of D-cycloserine for        from 29 days to 43 days.

In some embodiments, the invention provides for the use of D-cycloserinefor the preparation of a medicament/kit formulated to provide a dosageregimen as follows

-   -   a first dosage of 50-300 mg/day of D-cycloserine for from 1 to 5        days, followed by:    -   a second dosage of 300-600 mg/day of D-cycloserine for from 5 to        20 days, followed by:    -   a third dosage of from 600-800 mg/day of D-cycloserine for from        21 days to 28 days, followed by:    -   a fourth dosage of from 800-1200 mg/day of D-cycloserine for        from 29 days to 43 days for reducing the incidence or treating        suicide or suicide ideation in a subject or population, wherein        said D-cycloserine is formulated for oral administration.

In some embodiments, according to this aspect, the first dosagecomprises 250 mg/day of D-cycloserine for 3 days, and in someembodiments, the second dosage comprises 500 mg/day of D-cycloserine for18 days and in some embodiments, the third dosage comprises 750 mg/dayof D-cycloserine for 7 days and in some embodiments, the fourth dosagecomprises 1000 mg/day of D-cycloserine for 18 days, and in someembodiments, the first, second, third and fourth dosage comprise thatdescribed in accordance with this aspect.

In some embodiments, the method further comprises administering a secondtherapeutic agent for reducing the incidence or treating suicide orsuicide ideation in a subject or population. In some embodiments, themedicaments in accordance with the described uses of this inventionfurther comprises a second therapeutic agent for reducing the incidenceor treating suicide or suicide ideation in a subject or population.

According to this aspect, the method is not limited in terms of thetiming of the to administration of the second therapeutic agent, suchthat the methods of this invention contemplate a subject or populationalready treated with a second therapeutic agent, or a naïve subject orpopulation concomitantly treated with D-cycloserine and the secondtherapeutic agent, or in some embodiments, the subject or population isinitially treated with D-cycloserine and then administered a secondtherapeutic agent, and each of these scenarios represents an embodimentof this invention. Such second therapeutic agent will be any such agentas herein described, including a tetracyclic antidepressant (TeCA),selective serotonin reuptake inhibitor (SSRI), aserotonin/norephinephrine reuptake inhibitor (SNRI), an antipsychoticapproved for reducing the incidence or treating suicide or suicideideation in a subject or population or a combination thereof.

In some embodiments, in accordance with the methods of this invention,the regimen comprises administering a second therapeutic agent at adosage which is considered to be suboptimal for reducing the incidenceor treating suicide or suicide ideation in a subject or population whentreating said subject with said second therapeutic agent alone.

Guilt is a known surrogate marker for suicide, and as is demonstratedhereinbelow, a significantly greater (p=0.01) reduction in guilt wasobserved in patients administered D-cycloserine versus patientsreceiving placebo alone.

The present invention also contemplates that the methods of thisinvention for treating/reducing the incidence of depression and/orsuicide are also suitable, in particular, in a population exhibiting aminor allelic expression pattern for the GLDC gene consistent with atreatment resistant depression population. As described hereinbelow, anumber of the participants exhibited a genotype distribution consistentwith the elevated minor allele frequency in treatment resistantdepression, and such subjects were responsive to the therapeutic regimenadministered.

Thus the invention specifically contemplates, as certain embodiments ofthe same, that the methods and uses as herein described may bespecifically for a subject or population having a genetic predilectionto treatment-resistant depression.

In some embodiments, in accordance with the methods of this invention,the subject is provided with a pharmaceutically acceptable medicationdispensing package as herein described as part of the therapeuticmethod.

As described in Textbook of INTERNAL MEDICINE, Kelley, et al. (eds.),Part X: Neurology, Chapter 469: Major Psychiatric Disorders, (J.Lippincott Co., Philadelphia), pp. 2198-2199 (1992), depression canoccur throughout life and is at least twice as common in women as inmen. Patients often present without the subjective sense of beingdepressed but complaining of somatic symptoms of depression, mostcommonly fatigue, sleep disturbances, or impotence. Patients maydescribe feeling sad, blue, low, irritable, or anxious, as well as beingdepressed. Diagnosis of major depression is based either on a distinctchange of mood that is prominent, generally persists throughout the day,and occurs each day for at least 2 weeks or on markedly diminishedinterest or pleasure in most activities over a similar period. Thediagnosis requires that at least four of the following symptoms bepresent nearly every day for a period of 2 weeks: significant weightloss (or weight gain in some younger patients), prominent sleepdisturbance, agitation or retardation with slow speech, fatigue,feelings of worthlessness and guilt, slowed thinking, and hopelessness.

Depression can likewise be associated with the symptoms of disease(e.g., systemic lupus erythematosus) or as a side effect of thetreatment of disease (e.g., with antihypertensive therapy). One form ofdepression, postpartum depression, has been commonly found in womenduring the period following childbirth.

The methods and materials of this invention are therefore suitable fortreatment of depression or symptoms of depression associated with otherdiseases, as herein described.

Human clinical trials for the treatment of depression are well known inthe art, preferably in blinded studies evaluating subjects provided withblinded samples of the test active agent or placebo, and as describedbelow in the Examples.

Surprisingly, Applicants found highly beneficial treatment results whena dosage of 1000 mg/day was administered to the subjects. Accordingly,in one embodiment, this invention also provides a pharmaceuticalcomposition comprising D-cycloserine formulated for oral administrationproviding a dosage of 1000 mg/day.

According to this aspect, and in one embodiment, the invention providesa method for the treatment of depression in a subject, said methodcomprising orally administering 1000 mg/day of D-cycloserine to asubject in need thereof, wherein said subject has first beenadministered D-cycloserine at dosage of between 50-500 mg/day ofD-cycloserine for from 7 days to 21 says prior to administering said1000 mg/day or D-cycloserine.

In some embodiments, according to this aspect, the subject haspreviously been administered or is concurrently administered a secondtherapeutic agent for the treatment of depression.

In some embodiments, according to this aspect, the second therapeuticagent comprises any such agent as herein described, for example, atetracyclic antidepressant (TeCA), selective serotonin reuptakeinhibitor (SSRI), a serotonin/norephinephrine reuptake inhibitor (SNRI),an to antipsychotic approved for use in treatment of depression or acombination thereof.

In some embodiments, according to this aspect, the second therapeuticagent is administered at a dosage, which is considered to be suboptimalfor treating depression in said subject when treating said subject withsaid second therapeutic agent alone.

In some embodiments, according to this aspect, the invention furtherprovides for the use of D-cycloserine in the preparation of a medicamentformulated for oral administration at a dosage of 1000 mg/day for thetreatment of depression in a subject in need thereof.

A subject undergoing treatment with the methods of the invention canexperience significant improvements in depression. Relative to subjectstreated with alternative treatments for depression, subjects treatedaccording to the methods of the invention will experience, in someembodiments, greater improvement, or more long-lasting improvement, asmeasured by any clinically recognized assessment method for depression(e.g., the 21-item Hamilton Depression Rating Scale). It should be notedthat not every subject will benefit from the methods of the invention,just as other pharmaceutical agents do not typically benefit everypatient.

The following examples describe certain embodiments of the invention andshould not be construed as limiting the scope of what is encompassed bythe invention in any way.

EXAMPLES Example 1 Beneficial Effects of D-Cyloserine on MajorDepressive Symptoms in Treatment-Resistant Depression

Methods

This study was approved by the appropriate institutional review boards.Twenty-six patients meeting DSM-IV (Papp, M. and E. Moryl, Eur JPharmacol, 1996. 316(2-3): p. 145-51) criteria for major depressivedisorder and who were free of significant or unstable medical illnesswere enrolled in the study. Diagnosis was established on the basis ofsemi-structured psychiatric interviews, review of all available medicalrecords and confirmation by two board-certified psychiatrists. All ofthe patients were poorly responsive to treatment with antidepressantdrugs and have been receiving a stable therapeutic dose of an approvedantidepressant drug for at least 8 weeks before study entry, i.e. allpatients met criteria for refractory depression, defined as a >20 scoreon the 21-item HAM-D, despite at least 2 prior adequate antidepressantmedications (e.g. SSRIs, SNRIs, TCAs) trials during the currentdepression episode. Ongoing medication doses remained fixed throughoutthe study.

After complete description of the study, orally and in writing, written,informed consent was obtained from all participating patients. A randomassignment, double-blind placebo-controlled, parallel group design wasused in the study. After a 2 wk (week −2 to baseline) assessment period,subjects were randomly allocated to receive under double blindconditions either D-cycloserine or placebo for 6 wk. D-cycloserine orplacebo were given in addition to each patient's regular antidepressantmedication, the dose of which remained fixed throughout the study.D-cycloserine and placebo were administrated orally, in identicalcapsules, and according to the same dose escalation schedule. Plasmaglycine and serine levels were determined pre/post treatment for asubgroup of 20 subjects by HPLC. Results were compared to those ofnormal comparison subjects drawn from a previous study of glycine levelsin schizophrenia patients vs. controls using a demographically similarpopulation (Neeman et al., 2004)

A fixed, slow titration-high dose treatment schedule for adjuvanttreatment with D-cycloserine was conceptualized and used with allparticipating patients during the 6 wk study period: 250 mg/day for 3days ⋄ 500 mg/day for 18 days ⋄ 750 mg/day for one week ⋄ 1000 mg/day (1g/day) for two weeks.

Several scales were used throughout the study to assess the severity ofsymptoms and side effects in each patient. All the assessments wereperformed by a psychiatrist who was blind to the experimental treatmentassignment. HAM-D (1) was used at wk. −2, baseline and bi-weeklythroughout the study. HAM-A (3), BDI (2) and the Clinical GlobalImpression—Severity of Illness Scale (31) were used at baseline andbiweekly throughout the study. In addition to the symptoms sensitive topsychosis development that are included in HAM-D, overall side effectswere assessed at baseline and biweekly throughout the study using theUKU side effects rating scale for the registration of unwanted effectsof psychotropic drugs (32) BDI scores were available only for 20 of the26 study participants.

Primary data analysis was conducted by mixed-model regression using allavailable data. Subject id was coded as index variable, treatment week(0-6) as repeated measure, and treatment as fixed factor. A secondaryanalysis assessed effect size of change scores from baseline to end oftreatment based upon LOCF measures for all subjects. Significance ofchange across treatment week was evaluated using repeated measuresANOVA. Follow-up t-tests were performed to evaluate differentialresponse by older (TCA) vs. newer (TeCA, SSRI/SSRI) treatment.

Results

The demographic and clinical characteristics of the 26 patients thatparticipated in the study are summarized in Table 1.

TABLE 1 Demographic and Clinical Characteristics of the Sample*D-Cycloserine Placebo Total sample (N = 13) (N = 13) (N = 26) Age, y.52.8 ± 11.5 53.1 ± 9.4  53.0 ± 10.2 Male/Female 5/8 5/8 10/16 Maritalstatus 10/2/1 11/2/— 21/4/1 (Married/Divorced/ Widowed) Length ofillnes, y. 16.8 ± 14.6 12.6 ± 15.7 14.4 ± 14.4 Number of previous 3.3 ±1.0 2.8 ± 1.2 3.0 ± 1.1 episodes Duration of current episode, 14.0 ±17.1 12.3 ± 12.4 13.2 ± 14.3 mo. Baseline rating scale scores HAM-D 25.1± 5.6  27.2 ± 4.9  26.2 ± 5.4  HAM-A 27.6 ± 6.7  26.7 ± 5.8  27.2 ± 6.4 CGI-S 5.2 ± 0.4 5.3 ± 0.6 5.3 ± 0.5 BDI 35.3 ± 8.3  35.3 ± 7.5  35.3 ±7.6  *Values are mean ± SD for continuous variables and number ofsubjects for categorical values. HAM-D, 21 Item - Hamilton DepressionRating Scale; HAM-A, Hamilton Rating Scale for Anxiety; BDI, BeckDepression Inventory, Second Edition; CGI-S, Clinical GlobalImpression - Severity of Illness Scale

Patients were receiving the following medications, alone or incombination: mirtazapine (6), duloxetine (5), venlafaxine (4),escitalopram (2), citalopram (2), fluoxetine (1), paroxetine (1),mianserine (1), reboxitine (1), desipramine (1), clomipramine (1),imipramine (1), hypericum (1) clonazepam (3), low dose sulpiride (3),lorazepam (1), diazepam (1), oxazepam (1) and carbamazepine (1). Thecharacteristics of patients randomized to receive D-cycloserine did notdiffer from those of patients randomized to receive placebo. For allsubjects, depression symptoms, as reflected in HAM-D scores, were stablefor at least 2 wk prior to experimental treatment initiation (Table 2).

TABLE 2 HAM-D Scores Prestudy and at Experimental Treatment InitiationInitial Prestudy Initiation HAM-D score Assignment (wk −2) (baseline)Total D-cycloserine 25.3 ± 4.1  25.1 ± 5.6  Placebo 24.4 ± 3.8  27.2 ±4.9  Guilt D-cycloserine 2.3 ± 0.6 1.5 ± 0.9 Placebo 1.5 ± 1   1.4 ± 0.9Depersonalization/ D-cycloserine 0.7 ± 0.6 0.3 ± 0.9 DerealizationPlacebo 0.0 ± 0.0 0.0 ± 0.0 Paranoia D-cycloserine 0.3 ± 0.5 0.1 ± 0.3Placebo 0.0 ± 0.0 0.1 ± 0.3 *Values are mean ± SD. HAM-D, 21 item -Hamilton Depression Rating Scale

Thirteen patients were randomly allocated to receive adjuvantD-cycloserine treatment and thirteen patients were randomly allocated toreceive adjuvant placebo. A total of twenty two patients, ten in theD-cycloserine group and twelve in the placebo group completed the entirestudy. Four patients were withdrawn from the study: one in the placebogroup, due to complaints of chest pain, and three in the D-cycloserinegroup due to non-compliance, and complaints of ear aches and tiredness,respectively. Following withdrawal from the study, these complaintsceased. No other complaints were registered throughout the study and noD-cycloserine/placebo treatment side effects were noted using the UKUscale for rating side effects.

D-cycloserine treatment led to significant improvement in depressivesymptoms as measured by HAM-D (p=0.005) and the BDI (p=0.046) (Table 3).

Comparison by glycine levels: Pre-treatment plasma glycine levels forthe depression group as a whole (371.9±160.9 μM) were significantlygreater than those observed in age-matched normal comparison subjects(244.8±84.2 μM, p=0.002). Glycine levels post-treatment (339.0±97.3 μM)were not significantly different from pre-treatment levels. A cutofflevel of 300 μM significantly distinguished groups (Fisher exact testp=0.001).

When HAM-D change scores were analyzed as a function of pretreatmentglycine levels, including glycine <300 μM vs. ≧300 μM as a factor led toa significant treatment X glycine level interaction (p=0.043). Effectsize vs. placebo among patients with pretreatment glycine ≧300 μM (n=14)was extremely large (d=2.36), suggesting robust antidepressant effects.Similarly, 4 of 7 (57%) patients with pre-treatment glycine levels ≧300μM were remitters vs. only 1 of 5 (20%) of non-remitters, suggestingthat patients with elevated pretreatment glycine levels show unexpectedand particular sensitivity to glycine antagonist treatment.

TABLE 3 Symptom levels by treatment and week (mean ± SD) Outcome measureTreatment Week HAM-D Treatment Baseline Week 2 Week 4 Week 6 LOCF F¹ dfp d Total D-cycloserine 25.1 ± 5.6 17.8 ± 8.1 15.4 ± 10.9 11.6 ± 10.013.1 ± 9.4 8.49 1,80.7 0.005 0.91 Placebo 27.2 ± 4.9 22.8 ± 7.4 22.4 ±6.9 21.5 ± 8.7 23.3 ± 9.6 Guilt D-cycloserine  1.5 ± .9  1.1 ± 1.0  0.9± 1.0  0.4 ± .7  0.5 ± 0.8 0.32 1,93.9 0.6 0.89 Placebo  1.4 ± .9  1.2 ±.9  1.0 ± .9  0.9 ± .9  1.1 ± 1.0 Depersonalization/ D-cycloserine  0.3± 0.9  0.1 ± 0.3  0.0 ± 0.0  0.0 ± 0.0  0.0 ± 0.0 — — — 0.72Derealization Placebo  0.0 ± 0.0  0.0 ± 0.0  0.0 ± 0.0  0.0 ± 0.0  0.0 ±0.0 Paranoia D-cycloserine  0.1 ± .3  0.2 ± .4  0.2 ± .4  0.1 ± 0.3  0.2± 0.4 2.54 1,85.3 0.12 −0.31 Placebo  0.1 ± .3  0.1 ± .3  0.0 ± .0  0.0± 0.0  0.1 ± 0.3 HAM-A D-cycloserine 27.6 ± 6.7 19.0 ± 9.9 16.8 ± 10.012.2 ± 10.1 14.2 ± 9.8 3.27 1,89.2 0.074 0.85 Placebo 26.7 ± 5.8 22.7 ±7.2 21.1 ± 4.9 19.5 ± 5.8 21.0 ± 7.9 CGI-S D-cycloserine  5.2 ± 0.4  4.5± 0.9  3.8 ± 1.5  3.0 ± 1.7  3.4 ± 1.7 4.01 1,50.2 0.051 0.99 Placebo 5.3 ± 0.6  4.9 ± 0.8  4.9 ± 1.1  5.0 ± 0.8  4.8 ± 1.2 BDI D-cycloserine35.3 ± 8.3 28.3 ± 10.5 22.9 ± 13.2 18.4 ± 14.2 20.0 ± 14.1 4.13 1,71.70.046 0.95 Placebo 35.3 ± 7.5 29.6 ± 6.7 30.3 ± 6.1 27.9 ± 7.3 31.1 ±9.9 ¹Mixed model regression

Trends toward improvement were observed as well for anxiety, asreflected in the HAM-A (p=0.051) and overall level of function, asreflected in the CGI-S (p=0.076). No significant change was observed initems potentially reflecting psychosis, includingdepersonalization/derealization and paranoia, which remained negligiblein both treatment groups throughout the study.

Only one subject in the study (D-cycloserine group) had significantsuicidal ideation on study entry, as reflected in HAM-D suicide item(item 3)>2. In this subject, symptoms resolved within two weeks andremained reduced throughout the remainder of the study. No significanteffect on guilt feelings was observed in the primary analysis.Nevertheless a significantly greater to (p=0.01) reduction in guilt wasobserved in a completers analysis, with patients on D-cycloserine (n=10)showing a 1.3±0.5 pt reduction in guilt feelings vs. 0.4±0.9 in patientson placebo (n=11), also suggesting reduced suicide risk.

Responders analysis: Categorical analyses were conducted for responders,defined as 50% or greater reduction in HAM-D symptoms, and remitters,defined as HAM-D≦7. Seven of 13 (54%) patients assigned to D-cycloserinequalified as responders vs. 2 of 13 (15%) assigned to placebo (χ²=4.24,df=1, p=0.039). Five of 13 (38%) patients assigned to D-cycloserine alsowere considered remitters vs. 2 of 13 (15%) assigned to placebo,although this difference was not statistically significant (χ²=1.76,df=1, p=0.19).

TCA (n = 2) TCA SSRI/SNRI/TeCA Outcome (n = 2) (n = 11) Measure mean sdmean sd T df p % Responder  0.0 0.0 63.6 50.4 4.18 10.0 0.002 % Remitter 0.0 0.0 45.5 52.2 2.89 10.0 0.016 HAM-D 25.5 3.5 25.0 6.1  .16  2.3 .9(baseline) HAM-D (LOCF) 22.5 0.7 11.4 9.2 3.94 10.5 .002

Comparison by antidepressant type: Of the 13 patients randomized toactive treatment, 11 were being treated with newer antidepressantsincluding SSRIs/SNRIs or TeCAs, and 2 with TCAs. Comparison of responsebetween patients receiving older vs. newer antidepressants showed asignificantly higher response and remission rate among those receivingnewer antidepressants, as well as a between-group difference indepressive symptoms at week 21 using the HAM-D. In addition, both of thepatients receiving TCAs (100%) showed non-zero psychosis scores a week6, vs. 5 of 10 receiving newer antidepressants (50%). However, nosubjects were discontinued from either group because of psychoticsymptoms.

Genotype information for the rs10975641 locus of the GLDC enzyme wasobtained for 7 of the participants in the active treatment arm. Genotypedistribution was 1:3:3 for CC, CG, and GG genotypes, respectively,yielding minor allele (G) frequency of 0.64. This is consistent with theelevated minor allele frequency in treatment resistant depressionobserved by Ji et al. (2010). Among the 6 patients with minor allele(G), there was a 15.2±8.2 pt reduction in HAM-D symptoms vs. 3.8±9.8 ptsin the placebo group (p=0.025). Furthermore, 5/6 were responders (83.3%)vs. 2/13 (15%) in the placebo group (p=0.002).

The present study is the first to demonstrate antidepressant effects ofD-cycloserine or other glycine site antagonists in combination withantidepressants. Furthermore, they to demonstrate that such agents areparticularly effective when used with newer antidepressants such asTeCAs and SSRIs/SNRIs, which appear to have sufficient intrinsicantipsychotic efficacy to prevent psychotic reactions observed inearlier studies of high dose D-cycloserine in depression, andparticularly effective in depressed patients with elevated pretreatmentplasma glycine levels. The present study provides for the unexpectedfinding that the newer antidepressants such as TeCAs and SSRIs/SNRIswere sufficient to prevent psychotic symptoms, while not interferingwith the anti-deperessant response of the same.

In addition, this is the first study to test DCS in patients diagnosedwith major depressive disorder according to modern (DSM-IV) criteria.The ability of newer antidepressants to prevent psychotic reactionsreported in prior studies with D-cycloserine in depression suggests thatcombination treatments with newer antidepressants may be particularlyeffective. In addition, many antipsychotic agents such as quetiapine,risperidone and olanzapine are indicated in treatment of depression. Acombination of D-cycloserine and an antipsychotic would thereforeconstitute another embodiment of the invention.

While certain features of the invention have been illustrated anddescribed herein, many modifications, substitutions, changes, andequivalents will now occur to those of ordinary skill in the art. It is,therefore, to be understood that the appended claims are intended tocover all such modifications and changes as fall within the true spiritof the invention.

It will be understood by those skilled in the art that various changesin form and details may be made therein without departing from thespirit and scope of the invention as set forth in the appended claims.Those skilled in the art will recognize, or be able to ascertain usingno more than routine experimentation, many equivalents to the specificembodiments of the invention described herein. Such equivalents areintended to be encompassed in the scope of the claims.

All publications, patents, and patent applications mentioned herein arehereby incorporated by reference in their entirety as if each individualpublication or patent was specifically and individually indicated to beincorporated by reference. In case of a conflict between thespecification and an incorporated reference, the specification shallcontrol. Where number ranges are given in this document, endpoints areincluded within the range. Furthermore, it is to be understood thatunless otherwise indicated or otherwise evident from the context andunderstanding of one of ordinary skill in the art, values that areexpressed as ranges can assume any specific value or subrange within thestated ranges, optionally including or excluding either or bothendpoints, in different embodiments of the invention, to the tenth ofthe unit of the lower to limit of the range, unless the context clearlydictates otherwise. Where a percentage is recited in reference to avalue that intrinsically has units that are whole numbers, any resultingfraction may be rounded to the nearest whole number.

In the claims articles such as “a,”, “an” and “the” mean one or morethan one unless indicated to the contrary or otherwise evident from thecontext. Claims or descriptions that include “or” or “and/or” betweenmembers of a group are considered satisfied if one, more than one, orall of the group members are present in, employed in, or otherwiserelevant to a given product or process unless indicated to the contraryor otherwise evident from the context. The invention includesembodiments in which exactly one member of the group is present in,employed in, or otherwise relevant to a given product or process. Theinvention also includes embodiments in which more than one, or all ofthe group members are present in, employed in, or otherwise relevant toa given product or process. Furthermore, it is to be understood that theinvention provides, in various embodiments, all variations,combinations, and permutations in which one or more limitations,elements, clauses, descriptive terms, etc., from one or more of thelisted claims is introduced into another claim dependent on the samebase claim unless otherwise indicated or unless it would be evident toone of ordinary skill in the art that a contradiction or inconsistencywould arise. Where elements are presented as lists, e.g. in Markushgroup format or the like, it is to be understood that each subgroup ofthe elements is also disclosed, and any element(s) can be removed fromthe group. It should it be understood that, in general, where theinvention, or aspects of the invention, is/are referred to as comprisingparticular elements, features, etc., certain embodiments of theinvention or aspects of the invention consist, or consist essentiallyof, such elements, features, etc. For purposes of simplicity thoseembodiments have not in every case been specifically set forth in haecverba herein. Certain claims are presented in dependent form for thesake of convenience, but Applicant reserves the right to rewrite anydependent claim in independent format to include the elements orlimitations of the independent claim and any other claim(s) on whichsuch claim depends, and such rewritten claim is to be consideredequivalent in all respects to the dependent claim in whatever form it isin (either amended or unamended) prior to being rewritten in independentformat.

What is claimed is:
 1. A method of treating treatment-refractorydepression, comprising: administering D-cylcoserine at a dosage of 1000mg/day-2000 mg/day to a patient under treatment for depression whereinsaid patient is receiving either an approved antidepressant agentselected from the group consisting of tetracyclic antidepressants(TeCA), selective serotine reuptake inhibitors (SSRIs), andserotonin/norepinephrin reuptake inhibitors (SNRIs), or an antipsychoticagent approved for treatment of depression, wherein said patient istreatment-refractory, and wherein said patient is experiencing sideeffects from receiving said antidepressant or said antipsychotic agent.2. The method of claim 1, wherein said subject suffers from mania. 3.The method of claim 1, wherein said subject suffers from bipolardisorder.
 4. The method of claim 1, wherein said anti-depressant agentis ketamine.
 5. The method of claim 1, wherein said anti-depressantagent is an anti-NMDA agent.
 6. The method of claim 1, wherein saidsubject possesses a polymorphism for a GLDC allele.
 7. The method ofclaim 1, wherein said D-cycloserine is administered at a dosage of 1200mg/day-2000 mg/day.
 8. The method of claim 1 wherein either of saidantidepressant or antipsychotic agent is administered at a dosage amountthat is less than effective.
 9. The method of claim 1 wherein theadministration of said D-cycloserine and said antidepressant orantipsychotic agent is provided in a single pharmaceutical formulation.10. The method of claim 1 wherein the administration of saidD-cycloserine and said antidepressant or antipsychotic agent is providedas two separate pharmaceutical formulations.
 11. The method of claim 1wherein said D-cycloserine is administered separately with saidantidepressant or antipsychotic agent.
 12. A method of reducing the sideeffects of D-cycloserine in a human comprising: administeringD-cylcoserine at a dosage of 1000 mg/day-2000 mg/day together with aneffective amount of either an approved antidepressant agent selectedfrom the group consisting of tetracyclic antidepressants (TeCA),selective serotonin reuptake inhibitors (SSRIs), andserotonin/norepinephrin reuptake inhibitors (SNRIs), or an antipsychoticagent approved for treatment of depression to a patient, wherein saidpatient is refractory to treatment of depression.